Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism C. Rozas a , 1 , S. Loyola a , 1 , G. Ugarte a , M.L. Zeise b , M. Reyes-Parada c , d , F. Pancetti e , P. Rojas a , B. Morales a , ⁎ a Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile b Escuela de Psicología, Universidad de Santiago de Chile, Chile c Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Chile d Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile e Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Chile Received 30 June 2011; received in revised form 12 October 2011; accepted 25 November 2011 KEYWORDS MDMA; 5-HT; DA; Hippocampus; LTP; LTD Abstract 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3–CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT 2 serotonin receptors and postsynap- tic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA- dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP- dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synap- ses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals. © 2011 Elsevier B.V. All rights reserved. ⁎ Corresponding author at: Departamento de Biología, Facultad de Química y Biología. Universidad de Santiago de Chile. Alameda 3363, 40 Correo 33. Santiago, Chile. Tel.: +56 2 7181108; fax: +56 2 6812575. E-mail address: bernardo.morales@usach.cl (B. Morales). 1 These authors contributed equally to this work. 0924-977X/$ - see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.euroneuro.2011.11.010 Available online at www.sciencedirect.com www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2011) xx, xxx–xxx NEUPSY-10451; No of Pages 12 Please cite this article as: Rozas, C., et al., Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism, Eur. Neuropsychopharmacol. (2011), doi:10.1016/j.euroneuro.2011.11.010